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      Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy

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          Abstract

          Purpose

          To explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.

          Methods

          Patients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4–5 yrs of PEGV treatment.

          Results

          Among 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.0 ± 58.7 mg/dl at baseline, 116.4 ± 44.8 mg/dl at year 1 and 120.0 ± 44.3 mg/dl at yr 4. Mean HbA1c was 6.6 ± 1.2 % at yr 1 vs. 7.0 ± 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group ( n = 109), mean blood glucose decreased by 20.2 mg/dl at yr 4, mean HbA1c was 7.0 ± 1.5% at baseline vs. 6.8 ± 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs.

          Conclusions

          Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

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          Most cited references36

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          Medical progress: Acromegaly.

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            Factors influencing mortality in acromegaly.

            Studies of acromegaly have shown a doubling of mortality compared with the general population. With the development of new modalities of treatment, it has become important to identify prognostic factors relating to mortality. Between 1964 and 2000, 208 acromegalic patients were followed for a mean of 13 yr at Auckland Hospital. Treatment was by surgery or radionuclide pituitary implantation, and all except 27 patients received pituitary radiation. Over the duration of the study, 72 patients died at a mean age of 61 +/- 12.8 yr. Those dying were significantly older at diagnosis, had a higher prevalence of hypertension and diabetes, and were more likely to have hypopituitarism. The observed to expected mortality ratio (O/E ratio) fell from 2.6 (95% confidence interval, 1.9-3.6) in those with last follow-up GH greater than 5 microg/liter to 2.5 (1.6-3.8), 1.6 (0.9-3), and 1.1 (0.5-2.1) for those with GH less than 5, less than 2, and less than 1 microg/liter, respectively (P < 0.001). Serum IGF-I, expressed as an SD score, was significantly associated with mortality, with O/E mortality ratios of 3.5 (95% confidence interval, 2.8-4.2) for those with an SD score greater than 2, 1.6 (0.6-2.6) for those with an SD score less than 2 (normal or low levels), and 1.0 (0.1-3) for those with an SD score less than zero. When assessed by multivariate analysis, last serum GH (P < 0.001), age, duration of symptoms before diagnosis (P < 0.03), and hypertension (P < 0.04) were independent predictors of survival. If IGF-I was substituted for GH, then survival was independently related to last IGF-I SD score (P < 0.02), indicating that GH and IGF-I act equivalently as predictors of mortality. These findings indicate that reduction of GH to less than 1 microg/liter or normalization of serum IGF-I reduces mortality to expected levels.
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              Pasireotide Versus Octreotide in Acromegaly: A Head-to-Head Superiority Study

              Context: Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control. Objective: Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly. Design and Setting: We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries. Patients: A total of 358 patients with medically naive acromegaly (GH >5 μg/L or GH nadir ≥1 μg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging. Interventions: Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5μg/L and/or IGF-1 was above the upper limit of normal. Main Outcome Measure: The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 μg/L and normal IGF-1) at month 12. Results: Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% (P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 μg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%). Conclusions: Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.
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                Author and article information

                Contributors
                +33491383213 , Thierry.BRUE@ap-hm.fr
                Journal
                Endocrine
                Endocrine
                Endocrine
                Springer US (New York )
                1355-008X
                1559-0100
                24 November 2018
                24 November 2018
                2019
                : 63
                : 3
                : 563-572
                Affiliations
                [1 ]ISNI 0000 0001 2176 4817, GRID grid.5399.6, Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), ; 13005 Marseille, France
                [2 ]ISNI 0000 0004 0638 9491, GRID grid.411535.7, Assistance Publique-Hôpitaux de Marseille (AP-HM), Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l’hypophyse HYPO, ; 13005 Marseille, France
                [3 ]GRID grid.420142.1, Pfizer Health AB, ; Sollentuna, Sweden
                [4 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Medicine, , Erasmus University MC, ; Rotterdam, The Netherlands
                [5 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Women’s and Children’s Health, , Uppsala University, ; Uppsala, Sweden
                [6 ]ISNI 0000 0004 0645 1259, GRID grid.476633.3, European Medical Affairs, Pfizer, ; 1050 Brussels, Belgium
                [7 ]Practice for Endocrinology and Diabetes, Oldenburg, Germany
                [8 ]ISNI 0000 0000 8800 7493, GRID grid.410513.2, Endocrine Care, Pfizer Inc, ; New York, NY USA
                [9 ]Division of Clinical Endocrinology, Department of Medicine, Campus Charité Mitte, Berlin, Germany
                Author information
                http://orcid.org/0000-0001-8482-6691
                Article
                1792
                10.1007/s12020-018-1792-0
                6420440
                30474822
                9e579608-10fb-489c-9e9f-1842add52df7
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 13 March 2018
                : 12 October 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100004319, Pfizer;
                Categories
                Original Article
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2019

                Endocrinology & Diabetes
                acromegaly,diabetes,pegv,hba1c,igf-i,surveillance study
                Endocrinology & Diabetes
                acromegaly, diabetes, pegv, hba1c, igf-i, surveillance study

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